MYDRIATICS 

and 

BETA  AMINO  ACIDS 


By 

GLENN  FABER  ZELLHOEFER 

B.  S.  University  of  Illinois,  1921 


THESIS 

SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS 
FOR  THE  DEGREE  OF  MASTER  OF  SCIENCE  IN  CHEMISTRY 
IN  THE  GRADUATE  SCHOOL  OF  THE  UNIVERSITY 
OF  ILLINOIS,  1922 


URBANA,  ILLINOIS 


/ 9 2 2 
238 


ft. 


UNIVERSITY  OF  ILLINOIS 


a. 

01 


THE  GRADUATE  SCHOOL 


5V 


July  36,  -192-3* 


I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 

supervision  by Glenn  Faber  Zellhoefer . 

entitled Mydriatics  and  Beta-Amino  Acids 


BE  ACCEPTED  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 

the  degree  of Master  of  Science* 


Recommendation  concurred  in* 


o 


Committee 

on 

Final  Examination* 


•Required  for  doctor’s  degree  but  not  for  master’s 


Table  of  Contents. 


MYDRIATICS. 

Page 

Introduction  1. 

Experimental 1 . 

BET A- AMI NO  ACIDS. 

Introduction  5. 

Experimental  5. 

Bibliography 10. 


Digitized  by  the  Internet  Archive 

in  2016 


https://archive.org/details/mydriaticsbetaamOOzell 


Page  1. 

MYDRIATICS. 

Certain  compounds  of  the  general  formula  R.  C.R  OH  CHa  NR2# 

where  R represents  an  alkyl  or  aromatic  group,  have  mydriatic 

(1) 

properties.  The  following  compounds  of  this  general  formula 
were  synthesized  to  be  tested  for  their  mydriatic  properties: 

CH3  C Ph  OH.  CHa  N (Et)2,  C2H5.  C Ph  OH.  CH2  N (Et)2, 

C3H7.  C Ph  OH.  CH2  N (Et)2,  C4Hq.  C Ph  OH.  CH2  N (Et)2  and 
CH3  C Ph  OH.  CH2  N HCH3. 

EXPERIMENTAL  WORK. 

CH3.  C Ph  OH.  CH2  N ( Et ) 2 . 

An  equimolecular  amount  of  chi orace tone,  dissolved  in  ab- 
solute ether,  was  added  drop  by  drop  to  cold  phenyl  magnesium 
bromide.  After  warming  for  a short  while,  the  mixture  was  poured 
on  crushed  ice,  the  ether  layer  washed  with  water  containing  a 
few  cc.  of  sulphurio  acid,  and  the  product  distilled.  Under 
fifteen  millimeters  of  pressure,  the  Chlorhydrin  boiled  at  123 
to  135  degrees  C.  A yield  of  36$  of  the  theory  was  obtained. 

Diethyl  amine  was  dissolved  in  twice  its  volume  of  alcohol 
and  a little  less  than  one-half  the  molecular  amount  of  the 
chlor-hydrin  added.  The  mixture  was  warmed  on  a water  bath  for 
two  hours  then  most  of  the  alcohol  was  distilled  off  and  the  sol- 
ution made  acid  with  dilute  hydrochloric  acid.  After  wahsing 
with  benzene  to  remove  the  chlorhydrin,  the  aqueous  solution  was 
made  alkaline  with  sodium  hydroxide.  The  amino  alcohol  was  ex- 
tracted from  the  aqueous  solution  with  ether  and  distilled  under 
diminished  pressure. 


Page  3. 

An  analysis  for  nitrogen  gave  6.4 5$.  Specific  gravity  at 
38  degrees  C.  is  .978,  index  of  refraction  is  1.519  and  the 
boiling  point  is  133  to  135  degrees  C.  under  sixteen  millimeters 
of  pressure.  The  yield  wa3  48$  of  the  theory. 

C3H5.  C Ph  OH.  CH3  N (Et)3. 

Chloracetophenons,  dissolved  in  absolute  ether,  was  added 
slowly  to  a little  more  than  an  equivolecular  amount  of  ethyl 
magnesium  bromide.  During  the  addition  of  the  chloracetophenone 
the  temperature  was  kept  at  about  5 degrees  C.  but  after  the 
chloracetophenone  was  added  the  solution  was  warmed  on  a water 
bath  for  a half  hour.  The  solution  was  then  poured  on  crushed 
ice  and  the  ether  layer  washed  with  water  containing  a few  cc. 
of  sulphuric  acid.  The  ether  was  distilled  off  and  the  chlor- 
hydrin  distilled  under  diminished  pressure. 

The  boiling  point  of  the  C3H5.  C.  Ph  OH.  CH3  Cl  was  135 
to  130  degrees  C.  under  17  millimeters  of  pressure.  A yield  of 
33$  of  the  theory  was  obtained. 

The  chlorhydrin  was  treated  with  diethyl  amine  in  the  manner 
described  above  for  CH3  C.  Ph  OH.  CH3  Cl.  The  CH3  C.  Ph  OH.  CH3N(Et)  ls 
boiled  at  133  to  138  degrees  C.  under  15  millimeters  pressure. 

Index  of  refraction  was  1.503  and  specific  gravity,  .980  at  38°C, 

Upon  analysis  6.18 $ of  N was  found.  The  yield  was  30$  of  the 
theory. 

C3H7  C.  Ph  OH.  CH3  N (Et ) 2, 

The  chlorhydrin  C3H7  C.  Ph  OH.  CH3  Cl  was  prepared  by  treat- 
ing chloraoeto-phenone  with  propyl  magnesium  bromide  in  the 


Page  3 


manner  described  for  the  preparation  of  the  C2HS  C.  Ph  OH  CH2  Cl 
The  boiling  point  of  the  C3H7  C.  Ph  OH.  CH2  Cl  is  154  to  157 
degrees  C.  under  30  millimeters  of  pressure.  The  yield  ob- 
tained was  16$  of  the  theory. 

The  amino  alcohol,  C3H7  C.  Ph  OH.  CH2  N (Et)2,  was  prepared 
by  the  action  of  C3H7.  C Ph  OH.  CH2  Cl  on  diethyl  amine  in  the 
same  manner  as  described  for  the  preparation  of  CH3  C.  Ph  OH  CH2 
N (Et)a  from  CH3  C.  Ph  OH.  CH2  Cl. 

The  C3H7  C.  Ph  OH.  CH2  N (Et)a  boiled  at  145  to  147  degrees 
C.  under  30  millimeters  of  pressure.  The  index  of  refraction  is 
1.510  and  specific  gravity  .993  at  38  degrees  C.  The  yield  was 
13$  of  the  theory.  An  analysis  for  nitrogen  gave  5.8$. 

C4H9  C.  Ph  OH.  CH2  N (Et)s. 

C4Hg  C.  Ph  OH.  CHa  Cl  was  prepared  by  the  action  of  chlor- 
acetophenone  on  butyl  magnesium  bromide  by  the  same  method  as 
described  for  the  preparation  of  chlorohydrins.  The  C4Hg  C. 

Ph  OH.  CH2  Cl  boiled  at  135°  to  143  degrees  C.  under  15  millime- 
ters pressure.  The  yield  was  51$  of  the  theory. 

The  C4Hg  C.  Ph  OH.  CH2  Cl  was  treated  with  diethyl  amine 
and  the  C^g  C.  Ph  OH.  CH2  N (Et)2  obtained  boiled  at  169  to  173 
degrees  C.  under  ten  millimeters  of  pressure.  The  yield  was 
17$  of  the  theory.  The  index  of  refraction  is  1.501  and  specific 
gravity  .960  at  38  degrees  C.  An  analysis  gave  5.3$  N. 


. 


Paae  4 


CH3  C.  OH  Ph.  CH2  MH  CH3 

The  CH3  C.  OH  Ph  CHa  Cl  was  prepared  as  described  in  the 
first  section  of  this  paper. 

Fifteen  grams  of  the  chlor-hydrin  was  dissolved  in  twice 
its  volume  of  alcohol  and  methyl  amine  bubbled  through  the 
solution  for  three  hours.  The  process  for  the  isolation  of  the 
amino  alcohol  was  carried  out  as  described  in  the  other  prepar- 
ation but  no  trace  of  CH3  C.  Ph  OH  CH2  HH  CH3  was  found  in  the 
ether  extract.  In  the  benzene  extract  CH3  C.  Ph  OH.  CH2OH  was 
found,  indicating  that  the  chlorine  had  been  hydrolyzed  off 
during  the  process. 

Fifteen  grams  of  CH3  C Ph  OH.  CH2  Cl  was  dissolved  in  one- 
third  its  volume  of  alcohol  and  cooled  to  -13 °C. , while  methyl 
amine  was  passed  into  the  solution.  The  vessel  was  tightly 
stoppered  and  the  solution  allowed  to  stand  at  room  temperature 
over  night.  As  in  the  other  oases,  no  trace  of  amino  alcohol 
was  found  and  the  chlor-hydrin  suffered  hydrolysis. 

Ten  grams  of  the  CH3  C.  Ph  OH.  CHa  Cl  was  placed  in  a glass 
bomb  and  the  bomb  packed  in  carbon  dioxide  snow.  Seven  grams 
of  methyl  amine  was  distilled  into  the  bonb,  the  bomb  sealed  and 
heated  on  the  steam  bath  for  twenty-four  hours.  Only  a trace  of 
the  amino  alcohol  was  formed. 


Page  5 


BETA  AMINO  ACIDS. 

Introduction. 

At  present  there  is  no  satisfactory  method  for  the  production 

of  the  beta  amino  acids,  R C.  NHSH.  CH2  COOH.  In  this  work 

effort  was  made  to  treat  aceto  acetic  ester  with  ammonia  to 

(3) 

form  CH3  C :EH  CHa  COOC2H5  and  then  reduce  the  beta  amino 
crotonic  acid  ester  to  CH3  CH  NH2  CH2  COOCsHs  by  the  action  of 
hydrogen  under  pressure  in  the  presence  of  finely  divided  platinum.' 

Experimental  Part. 

For  the  production  of  the  beta  amino  crotonic  acid  ester 
the  procedure  as  given  by  J.  N.  Collie  (A.  336,  301)  was  followed. 
Dry  ammonia  gas  was  passed  into  a solution  of  one  part  aceto- 
acetic  ester  and  two  parts  dry  ether  at  zero  degrees  Centigrade. 

A white  crystalline  mass  was  formed,  as  described  by  Collie, 
which  was  proven  to  be  C6H]_3N03.  However  upon  standing  the 
CeH-^jNOs  did  not  split  out  water  to  form  C6H11N02,  as  Collie 
described,  but  a disintegration  into  ammonia  and  aceto  acetic 
ester  took  place,  slowly  at  zero  degrees  but  rapidly  at  room 
temperature.  An  exceptionally  high  grade  of  aceto-acetic  ester 
(B.P.  85°  -94°  C.  under  30  millimeters  pressure)  was  used  and  the 
ammonia  was  dried  by  passing  through  lime  towers  of  sodium 
hydroxide,  two  chilled  with  ice  and  the  third  chilled  with  carbon 
dioxide  snow.  Every  precaution  was  made  to  have  the  reacting 
mixture  dry  and  to  protect  it  from  moisture  during  the  reaction. 

But  even  with  these  precautions  the  procedure  was  unsuccessful. 
However  the  splitting  out  of  HOH  from  CeH-^gNOs  form  C6H11N02 
was  effected  by  keeping  a pressure  of  twenty  pounds  of  ammonia 


Page  6. 

over  the  C6H13N03  for  thirty-six  hours.  The  mixture  was  kept 
at  zero  degrees  centigrade.  When  this  method  was  used  a yield 
of  ninety-three  per  cent,  of  the  theory  was  obtained  even  though 
a mediocre  grade  of  acetoacetic  ester  was  used  and  no  effort 
made  to  dry  the  ammonia.  Upon  standing  three  months  some  of 
the  beta  amino  crotonic  acid  ester  decomposed  into  acetic  acid 
and  ammonia. 

To  effect  the  reduction  of  the  ethylic  beta  amido  crotonate 
to  form  beta  amino  butyric  acid  ester  the  unsaturated  product 
was  dissolved  in  twice  its  volume  of  alcohol  and  .5  grams  of 
platinum  oxide  (prepared  according  to  the  method  of  Voorhees  and 
Adams,  Journal  of  the  American  Chemical  Society,  June  1922, 
page  1397)  added.  The  mixture  was  agitated  for  forty-eight  hours 
under  a pressure  of  forty  pounds  of  hydrogen.  This  method 
proved  unsuccessful  so  the  solution  was  acidified  with  acetic 
acid.  This  likewise  failed  to  effect  reduction. 

The  hydrochloride  of  the  beta  amino  crotonic  acid  exter  was 
prepared  by  passing  perfectly  dry  hydrochloride  into  a solution 
of  25  grams  of  the  crotonate  and  25  grams  of  dry  ether,  (Soc. 

71,  303).  The  ether  was  then  decanted  off  and  absolute  alcohol 
added  with  .5  grams  of  the  platinum  oxide.  The  mixture  was 
agitated  under  about  forty  pounds  pressure  of  hydrogen  for  twenty 
hours.  About  .2  moles  of  H2  reacted.  The  product  was  filtered 
and  in  the  precipitate  was  ammonium  chloride  and  a compound 
which  proved  to  be  CeH13NOa 

This  compound  has  been  isolated  by  Collie  (Soc.  71,  303) 
and  identified  by  F.  N.  Fleiechman  (Soc.  91,  257)  as 


t 

. 


. 


Page  7. 


CHS 
C - 


H 

-N- 


■C:0 


C C — 

C:0  CH3 

oc2h5 


-C-H 


.3000  grams. 
.03138  B 
7.i 

7 . 3$ 


The  product  was  purified  by  recrystalization  from  hot  water. 
The  melting  point  was  138-139°Centigrade.  Analysis  for  the 
nitrogen  gave  the  following  results: 

Sampl e . . 3000  grams 

Nitrogen  .03156  w 

Per  Cent  of  N 7.13 $ 

Theory  7.3  # 

After  distilling  off  the  alcohol  in  the  filtrate  a resin- 
ous product  remained  which  was  water  insoluble  and  ether  soluble. 
It  suffered  decomposition  at  about  150°  when  effort  was  made 
to  distill  it  under  30  millimeters  of  pressure. 

Evidently  some  products  of  disintegration  of  the  crotonate 
hydrochloride  formed  a platinum  salt,  (Soc.  71,  303-311)  for 
the  theoreticel  amount  of  platinum  black  was  not  recovered  and 
the  resinous  material  derived  from  the  filtrate  contained  plat- 
inum as  indicated  by  tests  made  on  its  residues  after  ignition. 

In  hope  that  the  benzal  amino  crotonic  acid  ester  could 
be  reduced  without  suffering  rearrangement  it  was  prepared 
(B.  36,  467)  by  treating  equimolecular  amounts  of  benzal dehyde 
and  beta  amino  crotonic  acid  ester  and  heating  on  the  steam  bath 
for  fifteen  minutes.  The  benzal  amino  crotonic  acid  ester  is  a 
viscuous  product  which  suffers  decomposition  when  attempt  is 
m&de  to  distill  it  under  fifteen  millimeters  of  pressure.  No 


: 

' s< 

. 


• . 


• • 


t. 
> 

■- 


> 


Page  8 


effort  was  made  to  effect  its  reduction. 

Summary  and  Conclusion. 

While  it  is  possible  to  obtain  the  beta  amino  crotonic  acid 
ester  in  excellent  yields  by  the  action  cf  ammonia  upon  aceto 
acetic  ester  it  is  not  possible  to  effect  the  reduction  by  the 
action  of  hydrogen  under  pressure  with  platinum  as  a catalyst 
because  of  rearrangement  of  the  moleoule.  However  it  is  possible 
that  a derivative  of  the  beta  amido  crotonate,  or  some  homo- 
logue  can  be  satisfactorily  reduced  by  this  method. 


■ 


Page  9. 


ACKNOWLEDGEMENT. 

The  writer  wishes  to  acknowledge 
hie  indebtedness  to  Professor  Roger 
Adams,  who  proposed  these  problems,  and 
for  his  assistance  and  interest  during 
the  investigation. 


Page  10 


Bibliography. 

(1)  D.  R.  P.  169,746 

D.  R.  P.  189,481 

D.  R.  P.  101,175 


(3) 


Comptes  Rendus  138,  766-68. 


Ber. 

CO 

CO 

w 

3-1895,  p. 

Ber. 

11, 

1194. 

n 

15, 

1386 

N 

30, 

455,  3055. 

II 

32, 

544,  353 

It 

36, 

388 

II 

IB, 

619. 

Annalen, 

313,  173. 

n 

226,  301 

it 

314,  301 

Bielstein  I,  1206. 

Soo.  59,  173. 

Meyer  and  Jacobson,  vol.  1,  part  1,  p.  774. 
Soc.  71,  303. 

Soc.  91.  257 

J.  Amer.  Chem.  Soc.  v.  44,  No.  6,  1397 
Ber.  36,  467. 


